As the pile of failed Alzheimer’s disease programs grew ever larger, researchers identified trials in earlier- and earlier-stage patients as the key to efficacy. The flops were a case of right drug, wrong patients, the theory went. Eli Lilly put the idea to the test—and 10 years later has learned its drug was at fault all along.
The drug candidate in question is solanezumab, an antibody that targets soluble amyloid beta. Building on evidence that most clinical trials targeted patients too late in the disease pathway, Lilly began a study in 2013 to test solanezumab in people who had amyloid plaque accumulation in the brain, per PET scans, but were yet to develop symptoms. The 1,100 patients received solanezumab or placebo for 4.5 years.
Now, Lilly has released data from the study. Solanezumab failed to slow cognitive decline, and, as such, the trial missed its primary endpoint. The placebo arm numerically beat the solanezumab cohort across multiple endpoints.
The weak data may reflect the failure of solanezumab to act on the brain as hoped. Amyloid continued to accumulate in the brains of participants in both cohorts. While Lilly didn’t expect solanezumab to make a significant dent in deposited amyloid plaques, it had hoped the antibody would bind to soluble forms of the protein and slow the rate of accumulation.
To Reisa Sperling, M.D., a neurologist at the Brigham and Women's Hospital and Harvard Medical School as well as project director on the solanezumab study, the “data suggest that we may need to be more aggressive with amyloid removal even at this very early stage of disease.” The findings “indicate that amyloid is a key driver of cognitive decline at the preclinical stage of Alzheimer's,” Sperling said in a statement.
Lilly, which collaborated with groups including the National Institute on Aging on the trial, has already moved onto other assets. Solanezumab failed in advanced Alzheimer’s patients in 2012. When the drug also fell short in patients with mild disease four years later, Lilly dropped the asset. Lilly’s hopes in Alzheimer’s now rest on donanemab and remternetug.
The solanezumab failure comes nine months after another attempt to improve Alzheimer’s outcomes by treating early also came up short. For the other trial, Roche worked with partners to study crenezumab in cognitively unimpaired people at high imminent risk of developing Alzheimer’s based on their DNA. As happened at Lilly, Roche’s bid to move the needle by treating healthy individuals failed.